Structural basis of ASK1 inhibition by DJ-1

M. Horvath, O. Petrvalska, K. Psenakova, T. Obsil

Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University,
Hlavova 8, 12843 Prague 2, Czech Republic

horvath.mm@gmail.com

Human ASK1 (Apoptosis signal-regulating kinase 1) is a Ser/Thr kinase, belonging to subfamily of mitogen activated protein kinases (MAPKs). ASK1 is activated as a response to various stress stimuli, further transduces signal and activates response pathways playing role in apoptosis, differentiation, survival or immune response (1). During normal conditions ASK1 is tightly regulated mostly by its direct physiological inhibitors 14-3-3 and Thioredoxin (2). Recent studies, showed that a human protein/ nucleic acid deglycase DJ-1 is another important negative regulator of ASK1.

DJ-1 is a versatile enzyme playing role as an oxidative stress sensor, redox-sensitive chaperone, protease and transcription factor, forming dimers when activated. All enzymatic activities of DJ-1 lead to protection against oxidative stress and cell death (3,4). There are two models describing role of DJ-1 as a direct negative regulator of ASK1, however the exact molecular mechanism is not known (5).

Both, ASK1 and DJ-1 play important role in tissue homeostasis and cellular stress response, thus deregulation of their activity in human results in various diseases and cancer (6–8). Aim of this study is therefore: to describe regions of ASK1, DJ-1 and thioredoxin participating in the interaction and to provide a detailed molecular mechanism of ASK1 inhibition. Data obtained in this study can be further used to design drugs and therapeutic approaches to treat diseases caused by deregulated ASK1 activity.

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